Suicide ideation and male-female differences in major depressive disorder.

OBJECTIVE: This study aimed to explore male-female differences in suicide ideation (SI) and suicide risk factors in major depressive disorder (MDD). METHODS: We analysed 482 adults (sample 1) and 438 elderly outpatients (sample 2) with MDD. Sample 1 was treated with different antidepressant combinations (escitalopram; bupropion plus escitalopram; venlafaxine plus mirtazapine) and assessed by means of the Concise Health Risk Tracking (SI), Quick Inventory of Depressive Symptomatology, Altman Mania Rating Scale and Psychiatric Diagnostic Screening Questionnaire. Sample 2 was treated with venlafaxine and assessed using the Hamilton scale for depression, Anxiety Sensitivity Index and Penn State Worry Questionnaire for anxiety, Beck Scale for Suicide Ideation and Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: In sample 1, females had greater depression severity (O.R 0.961 99%CI: 0.929 - 0.995), males reported more alcohol abuse (O.R 1.299 99%CI: 1.118 - 1.509) and active SI (O.R 1.109 99%CI: 1.005 - 1.255). In sample 2 men showed more severe SI (O.R 1.067; 99%CI: 1.014 - 1.122) and weight loss (OR = 5.89 99%CI: 1.01 - 34.19), women more gastrointestinal symptoms. CONCLUSIONS: In these selected samples, although women had more severe depression, men had more suicide risk factors. Such differences might contribute to men's increased suicide risk.

In major depressive disorder sex differences affect the clinical expression of depressive episodes. In comparison to men, women endorse higher levels of overall depression in adult MDD and more somatic anxiety and gastrointestinal symptoms in late-life MDD.After controlling for confounding variables, males have more severe SI and a larger number of suicide risk factors (eg. alcohol abuse; weight loss). The association between male sex and SI is detectable in both adults and elderly patients with MDD.Further studies are necessary to elucidate how sex differences in suicide ideation and suicide risk factors are related to men's increased suicide risk.

Neurological, Metabolic, and Psychopathological Correlates of Lifetime Suicidal Behaviour in Major Depressive Disorder without Current Suicide Ideation.

INTRODUCTION: Suicidal behaviour (SB) has a complex aetiology. Although suicidal ideation (SI) is considered the most important risk factor for future attempts, many people who engage in SB do not report it. METHODS: We investigated neurological, metabolic, and psychopathological correlates of lifetime SB in two independent groups of patients with major depression (sample 1: n = 230; age: 18-65 years; sample 2: n = 258; age >60 years) who did not report SI during an index episode. RESULTS: Among adults (sample 1), SB was reported by 141 subjects (58.7%) and severe SB by 33 (15%). After controlling for interactions, four risk factors for SB emerged: male gender (OR 2.55; 95% CI: 1.06-6.12), negative self-perception (OR 1.76; 95% CI: 1.08-2.87), subthreshold hypomania (OR 4.50; 95% CI: 1.57-12.85), and sexual abuse (OR 3.09; 95% CI: 1.28-7.48). The presence of at least two of these factors had the best accuracy in predicting SB: sensitivity = 57.6% (39.2-74.5); specificity = 75.1% (68.5-82.0); PPV = 27.9% (20.9-37.2); NPV = 91.4% (87.6-94.1). In older patients (sample 2), 23 subjects (9%) reported previous suicide attempts, which were characterized by earlier onset (25 years: OR 0.95: 0.92-0.98), impaired verbal performance (verbal fluency: OR 0.95: 0.89-0.99), higher HDL cholesterol levels (OR 1.04: 1.00-1.07) and more dyskinesias (OR 2.86: 1.22-6.70). CONCLUSION: Our findings suggest that SB is common in major depressive disorder, even when SI is not reported. In these individuals it is feasible and recommended to investigate both psychiatric and organic risk factors. The predictive power of models excluding SI is comparable to that of models including SI.

Antidepressant emergent mood switch in major depressive disorder: onset, clinical correlates and impact on suicidality.

Antidepressant (AD)- emergent mood switch (AEMS) is a common complication of bipolar depression. This study aimed to investigate the prevalence and clinical correlates of subthreshold AEMS (i.e. not fulfilling DSM criteria for hypomanic episodes) in major depressive disorder (MDD) and, prognostically, its impact on AD treatment outcome and suicidality. The study involved 425 outpatients with MDD followed during the acute phase (12 weeks) and continuation (weeks 13-28) AD treatment. AEMS was assessed through the Altman Self-Rating Mania scale (ASRM ≥ 6). Several clinical features differentiated individuals with or without subthreshold AEMS (n = 204 vs. 221): negative self-perception [odds ratio (OR) 1.017-1.565]; panic disorder (OR 1.000-1.091); subthreshold hypomanic episodes (OR 1.466-13.352); childhood emotional abuse (OR 1.053-2.447); lifetime suicidal behaviour (OR 1.027-1.236); AD-related remission (χ 2  = 22.903 P  < 0.0001) and suicide ideation (χ 2  = 16.701 P  < 0.0001). In AEMS earlier onset showed a strong correlation with bipolar spectrum disorder (overall score: P  = 0.0053; mixed depression: P  = 0.0154; subthreshold hypomania: P  = 0.0150) whereas late-onset was associated with more severe suicidal behaviour ( P  < 0.001). In conclusion, our results demonstrate that subthreshold mood switches occur frequently in unipolar depression during acute AD treatment as well as in continuation phase. Time of switch onset seems to have the greatest diagnostic and prognostic value.

Age or age of onset: which is the best criterion to classify late-life depression?

In late-life depression (LLD), several differences between patients whose first episode is reported after age 65 (late-onset depression, LOD) and those with early-onset depression (EOD) might reflect the effects of brain ageing. To test this hypothesis, we analysed the impact of current age and age at illness onset on a number of clinical and cognitive manifestations in 438 outpatients with major depressive disorder aged >60 years, treated with venlafaxine for 12 weeks. When compared to the EOD group, patients with LOD were older ( P < 0.00001) and associated with lower depression severity ( P = 0.0029), lower global cognitive functioning [Mini-Mental State Examination (MMSE): P = 0.0001; Repeatable Battery for the Assessment of Neuropsychological Status: immediate memory, P = 0.0009, and delayed memory, P < 0.00001; Delis-Kaplan Executive Function System measuring executive functions: Trail-Making Test (TMT) - P = 0.0004 and Colour-Word Interference Test, Inhibition - P = 0.0063], and more dyskinesias (Abnormal Involuntary Movement Scale: P = 0.0006). After controlling for its interactions with age of onset, current age was inversely correlated with Montgomery Åsberg Depression Rating Scale scores at baseline ( P < 0.00001) and week 12 ( P = 0.0066), MMSE ( P < 0.00001), delayed memory ( P < 0.00001), and TMT ( P = 0.0021). Age of onset predicted impairment in immediate ( P = 0.023) and delayed memory ( P = 0.0181), and dyskinesias ( P = 0.0006). Although most features of LLD are related to ageing rather than to late-onset, LOD is a possible separate diagnostic entity characterised by memory dysfunction and increased liability to movement disorders.

Clinical correlates and prognostic implications of severe suicidal ideation in major depressive disorder.

Suicidal ideation (SI) is a risk factor for suicidal behaviour. To ascertain the clinical correlates and prognostic impact of severe SI, we analysed 249 outpatients with major depressive disorder (MDD) and suicidal thoughts included in the COmbining Medications to Enhance Depression outcome (CO-MED) trial. Patients with severe SI (36%) were younger at disease onset ( P = 0.0033), more severely depressed ( P = 0.0029), had more lifetime suicidal behaviour ( P < 0.0001) and psychiatric comorbidities (panic disorder: P = 0.0025; post-traumatic stress disorder: P = 0.0216), and a history of childhood maltreatment (neglect: P = 0.0054; emotional abuse: P = 0.0230; physical abuse: P = 0.0076; sexual abuse: P = 0.0016) than those experiencing low-moderate SI. After controlling for depression score, severe SI was positively correlated with lifetime suicidal behaviour (OR [95% CI]: 1.26 [1.12-1.41]), panic disorder (1.05 [1.00-1.12]), and childhood maltreatment (neglect: 1.93 [1.13-3.30]; physical abuse: 2.00 [1.11-3.69]; sexual abuse: 2.13 [1.17-3.88]), and inversely correlated with age of onset (0.97 [0.95-0.99]) and sleep-onset insomnia (0.76 [0.61-0.96]). Finally, the occurrence of serious lifetime suicidal behaviour was predicted by SI severity (2.18 [1.11-4.27]), bipolar score (1.36 [1.02-1.81]), and childhood sexual abuse (2.35 [1.09-5.05]). These results emphasise the importance of assessing childhood maltreatment and bipolar liability in MDD to estimate suicidal behaviour risk.

Clinical correlates and prognostic impact of binge-eating symptoms in major depressive disorder.

Binge-eating (BE) symptoms are relatively common in major depressive disorder (MDD), but their prognostic role is not fully understood. This study compared two groups of patients with MDD experiencing or not BE symptoms to ascertain differences in terms of clinical manifestations, presence of bipolar features, and antidepressant treatment outcomes. The study involved 482 outpatients collected within the Combining Medications to Enhance Depression Outcomes (CO-MED) trial, who were assessed with scales for depressive and hypomanic symptomatology, suicidality, comorbid mental disorders, and childhood traumas. BE symptoms were reported in 95 patients (20%). Patients with MDD experiencing BE symptoms were characterized by higher scores of negative self-outlook ( P = 0.0018), negative outlook of future ( P = 0.0014), irritability ( P = 0.0043), comorbid anxiety disorders (generalized anxiety disorder: P = 0.0006; panic disorder: P < 0.0001; social phobia: P < 0.0001), obsessive-compulsive disorder ( P = 0.0053), hypomanic symptoms (increased talkativeness: P = 0.0029; reduced need for sleep: P = 0.0171), and suicidality (suicidal propensity: P = 0.0013; suicidal risk: P = 0.0148; lifetime suicidal behavior: P = 0.0052). BE symptoms (OR = 2.02; 95% CI = 1.06-3.84) and depression severity (OR = 1.04; 95% CI = 1.00-1.08) were independently associated with lifetime attempted suicide. The presence of BE symptoms might indicate higher severity of depressive disorder. Suicidal risk is a major issue in these patients, whereas the association between BE and bipolar features needs further research.

Persistence of suicidal ideation within acute phase treatment of major depressive disorder: analysis of clinical predictors.

Suicidal ideation (SI) is common in major depressive disorder (MDD), and it is a risk factor for suicidal behaviour. Antidepressants are effective in reducing SI, but in some subjects, SI may persist for weeks. This study aimed to disentangle the contribution of baseline clinical characteristics in SI nonremission at week 6. Research involved 198 outpatients with MDD and SI collected within the Combining Medications to Enhance Depression Outcomes trial and treated with different antidepressant combinations. Although SI decreased from baseline to week 6 ( P < 0.0001), 78 patients (39%) failed to achieve SI remission. Insomnia [OR, 0.72; 95% confidence interval (CI), 0.52-0.99], reduced need for sleep (OR, 0.75; 95% CI, 0.58-0.99), self-confidence (OR, 0.52; 95% CI, 0.32-0.82), cheerfulness (OR, 0.57; 95% CI, 0.33-0.98), and comorbid panic disorder (OR, 0.93; 95% CI, 0.87-0.99) at baseline were associated with lack of SI remission after controlling for baseline depression and SI scores. The combination of baseline SI and insomnia was moderately effective in predicting the lack of SI remission, with a specificity of 80% (95% CI, 72-87%) and an NPV of 68% (95% CI, 63-72%). In individuals with MDD and SI, the presence of insomnia and bipolar features should prompt a search for more effective treatment solutions in order to favour SI remission and prevent suicidal behaviour.

Obsessive-compulsive symptoms in major depressive disorder correlate with clinical severity and mixed features.

Obsessive-compulsive symptoms (OCS) are often reported in patients with bipolar disorder. The aim of this study was to investigate OCS and their related clinical features in major depressive disorder (MDD). The analysis involved 482 outpatients with MDD collected within the Combining Medications to Enhance Depression outcomes trial, who were assessed with scales for depression, suicidality, irritability, hypomanic symptomatology, and other comorbid psychiatric manifestations. OCS were reported in 27% of the sample. Patients with MDD experiencing OCS were found to differ from those not experiencing OCS by a greater severity of depression (d = 0.41, P = 0.0001), more hypomanic symptoms (d = 0.48, P < 0.0001) and mixed features (22% vs. 10%, P = 0.001), increased levels of suicidal thoughts (d = 0.40, P = 0.0001), a lower likelihood of achieving remission after antidepressant treatment (19% vs. 33%, P = 0.0109), as well as more comorbid anxiety disorders (i.e. panic disorder: d = 0.98, P < 0.0001; generalized anxiety disorder: d = 0.74, P < 0.0001; social phobia: d = 0.71, P < 0.0001), and post-traumatic stress disorder (d = 0.81, P < 0.0001). In light of these findings, clinicians should pay more attention to the occurrence of OCS in MDD, as these symptoms may reflect greater clinical severity, poorer treatment outcome, and increased risk for bipolarity.

Post-traumatic stress disorder and childhood emotional abuse are markers of subthreshold bipolarity and worse treatment outcome in major depressive disorder.

Post-traumatic stress disorder (PTSD) and childhood maltreatment (CMT: parental neglect; emotional, physical and sexual abuse) have been linked to bipolar disorder but they are also common in major depressive disorder (MDD). Our objective was to investigate their association with the bipolar spectrum and antidepressant treatment outcome in 482 outpatients with DSM-IV MDD treated in the Combining Medications to Enhance Depression Outcomes trial for 28 weeks Bipolar spectrum score included age of onset <21 years, subthreshold hypomania (a period of elated or irritable mood with at least two concurrent hypomanic symptoms, which did not fulfill DSM criteria for hypomanic/manic episode) and depressive mixed state (DMX). PTSD subjects (n = 107; 22%) had more severe depression (P < 0.0001), work and social impairment (P = 0.0031), comorbid anxiety disorders (P < 0.0001) and increased suicidality (P = 0.0003). Bipolar spectrum score was higher with PTSD comorbidity (P = 0.0063) and childhood emotional abuse (P = 0.0001). PTSD comorbidity was associated with residual suicidality (P = 0.0218) after 6 weeks of antidepressant use whereas childhood emotional abuse [odds ratio (OR), 1.01-2.22], subthreshold hypomania (OR, 1.04-4.09) and DMX (OR, 1.00-4.19) were predictors of mood switch. These results corroborate the role of PTSD and childhood emotional abuse as markers of bipolar spectrum and prognostic factors during antidepressant treatment.

Irritable Mood and Subthreshold Hypomanic Episodes Correlate with More Severe Major Depression.

INTRODUCTION: Irritable mood (IM) and subthreshold hypomanic symptoms are reported in half and two-fifths of major depressed subjects respectively, but their clinical and prognostic meanings remain unclear. The aim of this study was to test the clinical usefulness of 2 specifiers in DSM-IV major depressive disorder (MDD): IM occurring during an index episode (IM+) and lifetime episodes of elated mood or IM with at least 2 concurrent hypomanic symptoms (subthreshold hypomanic episodes [SHEs]). METHOD: We included 482 outpatients with MDD participating in the Combining Medications to Enhance Depression Outcome study (mean age 43.14 ± 12.46 years, 144 males - 30%). The main aim of the original study was to test whether 2 different medications when given in combination as the first treatment step, compared to 1 medication, would improve antidepressant response. RESULTS: IM + subjects (N = 349; 70%) were younger and more often females, with a more severe depression, a more marked social impairment, and more psychiatric comorbidities. The IM + group was also characterized by higher levels of suicidal ideation and more cases of emotional abuse. The combination of IM+ and SHEs was associated with an even more severe clinical picture. Limitations include the post hoc method, incomplete assessment of bipolar validators (e.g., family history of bipolar illness), personality disorders and suicide attempts. CONCLUSIONS: The presence of IM and SHEs in MDD correlate with an overall more severe clinical condition.

Attrition in treatment-resistant depression: predictors and clinical impact.

The aim of this study was to investigate attrition (dropout) during a second antidepressant trial in treatment-resistant depression. Three hundred forty-two outpatients with major depressive disorder and lack of response to a prior antidepressant were treated with venlafaxine for 6 weeks. Sociodemographic and clinical characteristics were compared between the attrition and non-attrition groups. Attrition was reported in 65 patients (19%), of whom 30 patients (46%) dropped out within week 4. The characteristics of dropout patients included a longer duration of depressive episode (P = 0.011) and lower antidepressant doses (P < 0.0001) as a consequence of a faster decrease (week 2) in depressive symptoms (P = 0.028). However, by controlling for early improvement, dropout subjects were associated with a smaller probability of antidepressant response (odds ratio = 0.16▪.83). A decrease of at least 30% in Montgomery Asberg Depression Rating Scale on day 14 predicted subsequent dropout with high specificity (81.9%▪1.0%) but lower sensitivity (19.6%▪2.8%) for clinical use. Patients who have been depressed for a longer period and show an initial improvement of symptoms after changing their antidepressant may be at increased risk for drop out. Further studies are necessary to ascertain the usefulness of these characteristics for predicting attrition.

Early improvement and response to antidepressant medications in adults with major depressive disorder. Meta-analysis and study of a sample with treatment-resistant depression.

BACKGROUND: Initial improvement in the first weeks of antidepressant (AD) treatment is a useful early predictor of complete AD response. We performed a meta-analysis of AD studies to investigate whether a partial decrease in depressive symptoms by week 4 was associated with response and remission by weeks 6-14 in major depressive disorder (MDD). Finally, we focused on treatment-resistant depression (TRD: lack of response to prior AD) to test the impact of early improvement on a second AD treatment outcome and to compare different switching strategies. METHODS: Meta-analysis was conducted on AD naturalistic studies published between 01.01.2000 and 06.30.2017. TRD was an exclusion criterion. TRD was analyzed in 407 MDD patients treated with venlafaxine for 6 weeks. The MADRS was used to define very early improvement (VEI: > 20% decrease at week 2), early improvement (EI: > 30% decrease at week 4) and remission (week 6 MADRS < 10). A theoretical model was used to simulate AD switch in TRD patients who failed to achieve remission (Algorithm A), VEI (Algorithm B) or EI (Algorithm C). RESULTS: Our meta-analysis (9 studies; N = 6185) showed significant associations between early improvement, response (OR: 3.28 95% C.I: 2.06-5.20) and remission (OR: 2.10 95% C.I: 1.53-2.87). 24.6% of TRD sample remitted. VEI was a poor outcome predictor: sensitivity = 0.52 (0.40-0.63); specificity = 0.82 (0.76-0.86); AUC = 0.67 (0.62-0.71). EI had a moderate predictive power: sensitivity = 0.87 (0.77-0.93); specificity = 0.71 (0.66-0.77); AUC = 0.76 (0.71-0.80). The best treatment scenario was Algorithm C (switch after 4 weeks) in which remission rate was marginally increased (35.1% vs 33.7% of Algorithm A). Algorithm B (switch after 2 weeks) led to a 4.3% decrease in remission compared to Algorithm A. LIMITATIONS: Inclusion of a naturalistic sample without a control arm; simulation of treatments. CONCLUSION: Although literature data suggest a correlation between an initial improvement of depressive symptoms and later response and remission during AD treatment, our analysis shows that such an early improvement is not a reliable outcome predictor in TRD. The nature of TRD is complex and different biological mechanisms and treatments might be necessary for TRD patients.

Persistent benefits of slow titration of paroxetine in a six-month follow-up.

OBJECTIVE: Paroxetine titration may be difficult in older individuals as they are more sensitive to side effects. The current study extends to 6 months our previously published report in which paroxetine was started at 2.5 mg/day and slowly increased by 2.5 mg on alternate days (slow titration) or rapidly titrated to target dose from 10 mg/day (standard titration) in a naturalistic setting. METHODS: Here, the follow-up period was extended to 26 weeks. We performed an intent-to-treat analysis of 47 subjects from the original sample (major depressive disorder and/or generalized anxiety disorder (GAD); >60 years of age). Missing evaluations were replaced by last observations carried forward. GAD was included as a stratification factor. RESULTS: Patients in whom paroxetine was slowly up-titrated were more likely to remit (84.0% vs 54.5%; p = 0.028) and had lower core depression (p = 0.0015) and psychic anxiety levels (p = 0.006) after 26 weeks. Dropout rate was 20% in the slow titration group compared with 77.3% in the standard titration arm (p < 0.001). Patients with GAD accounted for all significant associations. No substantial differences were reported between slow and standard titration groups in the subsample without GAD. CONCLUSIONS: Despite some limitations, these findings suggest that paroxetine treatment should be started at lower doses in older depressed patients and slowly up-titrated. This strategy would allow to increase antidepressant response and the likelihood of completing treatment cycle in patients with high anxiety levels and GAD comorbidity.

Benefit of slow titration of paroxetine to treat depression in the elderly.

OBJECTIVE: Paroxetine is commonly used to treat depression in the elderly; however, titration issues have been raised. Rapid titration may lead to increased anxiety and early dropout. The aim of this cost-utility analysis was to compare the potential benefit of standard (10 mg the first day) versus slow titration (2.5 mg gradually increased). METHODS: Clinical analysis was based on a naturalistic trial integrated with a decision-analytic model representing second treatments for those who initially did not respond and for dropout cases. Treatment setting was a public outpatient center for mental disorders in Italy. Service use data were estimated from best practice guidelines, whereas costs (Euros; 2012) were retrieved from Italian official sources. RESULTS: Slow titration approach produced 0.031 more quality-adjusted life years (remission rate: 57% vs 44% in standard titration group) at an incremental cost of €5.53 (generic paroxetine) and €54.54 (brand paroxetine syrup). Incremental cost-effectiveness ratio (ICER) values were €159 and €1768, respectively, in favor of slow titration approach. Cost-effectiveness threshold, defined as ICER < 1 GDP per capita according to World Health Organization criteria, is about €25 000 in Italy. CONCLUSIONS: Our results are consistent with a superiority of slow titration of paroxetine in older depressed patients. However, these findings, in part based on simulated data, need to be replicated in clinical trials.

Challenging sequential approach to treatment resistant depression: cost-utility analysis based on the Sequenced Treatment Alternatives to Relieve Depression (STAR(⁎)D) trial.

In major depression, when a first antidepressant does not cause remission of symptoms (60%-75%), there are several options for continuing treatment in the next step. This study is a cost-utility analysis (CUA) of different second-line approaches. In a simulated trial outpatients with MDD were treated with citalopram for 13 weeks (level 1), then based on two alternative algorithms implemented from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study. Algorithm A: citalopram was continued until study endpoint (week 26). Algorithm B: patients who remitted during level 1 continued citalopram. Those who did not remit could opt for switching to another antidepressant (venlafaxine; sertraline) (b1) or adding bupropion to citalopram treatment (augmentation; b2). Algorithm B increased remission rate by 10.6% over Algorithm A (number needed to treat: 9.9; sensitivity range: 9.1-12.5). As a comparison, differences between active antidepressants and placebo are associated with NNT values of 6 to 8. In CUA Algorithm B was dominant with an ICER of $11,813 (sensitivity range=$1783 - $21,784), which is <1GDP per capita cost-effectiveness threshold (USA=$47,193). Among Algorithm B options, switching (b1) dominated Algorithm A with a smaller number of responders than augmentation approach (b2) (NNT 11 vs. 7.7), whereas ICER values were similar (b1: $14,738; b2: $15,458). However we cannot exclude a bias in selecting second treatment. This cost-utility analysis shows (in line with current guidelines) a benefit in modifying antidepressant treatment if response to first-line agent does not occur within 3 months, but not a clear-cut evidence in terms of NNT.

Effects of SORL1 gene on Alzheimer's disease. Focus on gender, neuropsychiatric symptoms and pro-inflammatory cytokines.

It was suggested that the gene encoding for sorLa, (SORL1) may affect Alzheimer's disease (LOAD) through a female-specific mechanism. The aims of this study were to confirm the role of gender in modulating the association between SORL1 and LOAD and to ascertain the influence of SORL1 on cognitive impairment, neuropsychiatric symptoms (BPSD) and secretion of pro-inflammatory cytokines. Ninety six outpatients with LOAD and 120 unrelated controls were genotyped for APOE and three SNPs at the 5' end of SORL1(intron 6): SNP 8 (rs668387); SNP 9 (rs68902); SNP 10 (rs641120). Clinical evaluation was made with the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). ELISPOT assays were used to measure pro-inflammatory cytokine (TNF-alpha; IL-6; IL-1beta; IFN-gamma) production in peripheral blood mononuclear cell (PBMC) supernatant from AD patients. SORL1 SNPs were not associated with LOAD in overall sample. Instead the G-alleles at SNPs 9 (p=0.015) and 10 (p=0.015) and the CGG haplotype (p=0.02) were associated with LOAD in the women subgroup. The TAA haplotype was marginally protective in AD patients being associated with lower BPSD scores (p=0.01). The same haplotype was also associated with higher IL-1beta (p=0.01) production. These genetic effects were not modified by APOE4 allele and controlled for illness duration and treatment. In conclusion, SORL1 does not appear to be a major risk factor for LOAD. Its contribution could be underestimated in our small sample. Sex-specific factors could modulate the association between SORL1 and AD. The influence of SORL1 variants on production of inflammatory cytokines warrants further investigation.

Catechol-o-methyltransferase and Alzheimer's disease: a review of biological and genetic findings.

Alzheimer's disease (AD) is the leading cause of dementia worldwide and is associated with a marked individual, familial and social burden. Catechol-O-mehyltransferase (COMT) is surfacing with a prominent role in AD pathophysiology by affecting the metabolism of catecholamine neurotransmitters and estrogen. COMT gene regulates dopamine levels in the prefrontal cortex which are involved in working memory and executive functioning. Impaired executive functioning is reported in a subgroup of AD patients and is associated with a more severe disorder, a more rapid disease progression and a shorter survival. The COMT rs4680 gene polymorphism has been investigated as a susceptibility factor for AD. No statistically significant results were found in meta-analysis but one study reported that the rs4680 Val allele was associated with AD-related psychosis. The COMT rs4680 polymorphism was also found to modulate declarative episodic memory in normal people and schizophrenic subjects. COMT inhibitors, that are adjunctive drugs in Parkinson's disease treatment, lower homocysteine levels and improve executive memory processes in normal subjects. A preliminary study, which needs replication, demonstrates that COMT inhibitors block beta-amyloid fibrils in vitro. Taken together, these findings suggest that research should focus on the role of COMT in AD pathogenesis and on the feasibility of targeting COMT activity in AD treatment.